The invention relates to 3-hydroxypyridine-2-carboxamidoesters, their preparation and their use for the inhibition of collagen biosynthesis and their use as pharmaceuticals for the treatment of fibrotic disorders.
Compounds which inhibit the enzymes prolyl and lysyl hydroxylase cause a very selective inhibition of collagen biosynthesis by affecting the collagen-specific hydroxylation reactions. In the course thereof, protein-bound proline or lysine is hydroxylated by the enzymes prolyl or lysyl hydroxylase. If this reaction is suppressed by inhibitors, a nonfunctional, underhydroxylated collagen molecule results, which can be released into the extracellular space only in a small amount by the cells. The underhydroxylated collagen additionally cannot be incorporated into the collagen matrix and is very easily proteolytically degraded. As a result of these effects, the amount of extracellularly deposited collagen is decreased overall.
Inhibitors of prolyl hydroxylase are therefore suitable substances in the therapy of disorders in which the deposition of collagens decisively contributes to the clinical picture. These include, inter alia, fibroses of the lung, liver and skin (scleroderma and scars after burns, injuries and surgical interventions) and also atherosclerosis.
It is known that the enzyme prolyl hydroxylase is effectively inhibited by pyridine-2,4- and -2,5-dicarboxylic acid (K. Majamaa et al., Eur. J. Biochem. (1984), 138: 239-245). In cell culture, however, these compounds are only active as inhibitors in very high concentrations (Tschank, G. et al., Biochem. J. (1987), 238: 625-633).
Prodrugs of the pyridine-2,4(5)-dicarboxylates are also known. These are described in the patent applications Ser. Nos. EP-A-O 590 520, DE-A42 38 506, and EP-A-O 562 512. N-Oxalylglycines as inhibitors of prolyl-4-hydroxylase are known from J. Med. Chem. (1992), 35: 2652-2658 (Cunliffe et al.) and EP-A-O 457 163. 3-Hydroxypyridine-2-carboxylic acid (glycyl)amides and their prodrugs, and their use, are disclosed in EP-A-O 661 269. Furthermore, 3-hydroxypyridine-2-carboxylic acid ((glycyl) ethyl ester)amide is described in J. Org. Chem. (1966), 31: 636-638.